In the war against AIDS, the chief enemy these days is resistance. Two decades after the first drug, AZT, was approved, there are now 27 HIV medications in four classes, with a first-in-class-five integrase inhibitor due from Merck this fall and several new classes heading for the homestretch. The transformation of this deadly disease into a manageable condition in the developed world has been a stunning achievement—but one relentlessly eroded by the ever-evolving-and-mutating virus. "You've got these patients who did well and you're excited for them," veteran HIV doctor and researcher, Harvard's Jerome Groopman, told the Wall Street Journal last year. "Then you get back with them and they have 12 mutations. You're desperately searching. They're hanging on by a thread."

Year after year tens of thousands of patients in the United States, and countless more worldwide, come to the end of their treatment hope. While statistics vary widely, the average first-line, three-drug combo starts failing after about seven years, while HIV begins to break through second and third regimens after about four and a half and four years, respectively. A decade after the protease revolution literally raised thousands of Lazaruses from their deathbeds, the increasingly urgent need is not simply to disable the virus but to block or even reverse the process of resistance itself.

Glenn Mattes

At this new front, no company is leading more boldly at the moment than Tibotec, a biotech born in Belgium in 1994 and bought in 2002 for $320 million by Johnson & Johnson. With a visionary "resistance to resistance" angle on drug development, the little company is on a big roll. Its first drug, Prezista (darunavir), a protease inhibitor, went from Phase II through accelerated approval last year; now with two non-nucleosides, etravarine, in Phase III, and rilpivirine, in Phase II, Tibotec is set to help launch a second revolution in HIV treatment—and make a run at Glaxo, BMS, and Abbott, the longtime market kingpins.

But if Tibotec succeeds, it will be partly because of its ability to resist another kind of resistance—resistance to the influence and interests of outsiders, most notably patients and the activists who represent them. For if the story of Tibotec is about original science, it is even more about the innovative strategies it has pursued based on the input it got when it opened its doors to a group of people who have traditionally been viewed as pharma's adversaries. Tibotec has focused on the real-world needs of patients, in the process defining the true value of its drugs, winning FDA approval and formulary uptake in near-record time, bucking a trend of price escalation, and, in the words of Martin Delaney, the nation's foremost AIDS activist, acting like "both a scientific leader and a civic leader." As the industry's drug giants scramble to rediscover their lost productivity, their leaders could do worse than learning from Tibotec.

Joining the Resistance

Targeting resistance was the inspiration behind Tibotec. The biotech got its start in a "resistance lab" founded in 1994 by Belgian scientist-cum-entrepreneur Rudi Pauwels. Three years later, Paul Stoffels, an AIDS doctor who did ground-breaking work in Africa before switching tracks to concentrate on HIV R&D at Janssen, teamed up with Pauwels to divide the fast-growing firm into two entities, drugmaker Tibotec and Virco, which had developed the first-ever database of every possible HIV mutation followed by the first-ever diagnostic test for HIV resistance. Immediate demand for the test, which fingers the mutation pattern and drug susceptibility of a patient's virus, was huge because it turned the guesswork of a mortal treatment decision into an exact science.

"Rudi saw the far-reaching implications of resistance before many others," says Roger Pomerantz, MD, president, of Tibotec R&D and the global head of virology. "He and Paul realized that to be true innovators in HIV, they needed to focus on where the medical need would be in 10 or 15 years—and they were exactly right."